This invention relates to purine derivatives. More particularly, this invention relates to N-[(purin-2-yl)methyl]sulphonamide derivatives and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such derivatives.
These derivatives are selective, functional agonists of the human adenosine A2a receptor and may be used as anti-inflammatory agents in the treatment of, inter alia, diseases of the respiratory tract.
Adenosine is a ubiquitous molecule having a central role in mammalian intermediary metabolism. Independently, adenosine acts on multiple surface receptors to produce a variety of responses. Adenosine receptor classification has revealed the presence of at least four subtypes: A1, A2a, A2b and A3. Stimulation of adenosine A2 receptors on the surface of human neutrophils has been reported to potently inhibit a range of neutrophil functions. Activated neutrophils can damage lung tissue by release of reactive oxygen species, for example, superoxide anion radicals (O2xe2x88x92), and granule products, for example, human neutrophil elastase (HNE), amongst other inflammatory mediators. In addition, activated neutrophils perform both de novo synthesis and release of arachidonate products such as leukotriene B4 (LTB4). LTB4 is a potent chemoattractant that recruits additional neutrophils to the inflammatory focus, whereas released O2xe2x88x92 and HNE adversely affect the pulmonary extracellular matrix. The A2 receptor subtype mediating many of these responses (O2xe2x88x92 and LTB4/HNE release and cell adhesion) is established as A2a. The A2 subtype (A2a or A2b) mediating the other effects remains to be established.
Selective agonist activity at the A2a receptor is considered to offer greater therapeutic benefit than the use of non-selective adenosine receptor agonists because interaction with other subtypes is associated with detrimental effects in the lung in animal models and human tissue studies. For example, asthmatics, but not non-asthmatics, bronchoconstrict when challenged with inhaled adenosine. This response is at least in part due to the activation of the A1 receptor subtype. Activation of A1 receptors also promotes neutrophil chemotaxis and adherence to endothelial cells, thus promoting lung injury. Furthermore, many patients with respiratory disease will be co-prescribed xcex22-agonists, and negative interaction has been shown in animal studies between isoprenaline and adenosine receptors negatively coupled to adenylate cyclase. Degranulation of human mast cells is promoted by activation of adenosine A2b receptors, thus selectivity over the A2b receptor is also advantageous.
We have now surprisingly found the present purine derivatives inhibit neutrophil function and are selective agonists of the adenosine A2a receptor. They may also have antagonist activity at the adenosine A3 receptor. The present compounds may be used to treat any disease for which an adenosine A2a receptor agonist is indicated. They can be used to treat a disease where leukocyte (e.g. neutrophil, eosinophil, basophil, lymphocyte, macrophage)xe2x80x94induced tissue damage is implicated. They are useful as anti-inflammatory agents in the treatment of diseases of the respiratory tract such as adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, bronchiectasis, chronic sinusitis and rhinitis. The present compounds may also be used in the treatment of septic shock, male erectile dysfunction, hypertension, stroke, epilepsy, cerebral ischaemia, peripheral vascular disease, post-ischaemic reperfusion injury, diabetes, rheumatoid arthritis, multiple sclerosis, psoriasis, dermatitis, allergic dermatitis, eczema, ulcerative colitis, Crohns disease, inflammatory bowel disease, Heliobacter pylon gastritis, non-Heliobacter pylon gastritis, non-steroidal anti-inflammatory drug-induced damage to the gastro-intestinal tract or a psychotic disorder, or for wound healing.
Accordingly, the present invention provides a compound of the formula: 
or a pharmaceutically acceptable salt or solvate thereof, wherein
R1 is hydrogen or C1-C6 alkyl optionally substituted by 1 or 2 substituents each independently selected from phenyl and naphthyl, said phenyl and naphthyl being optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, halo or cyano;
A is a bond or C1-C3 alkylene;
R2 is (i) hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, phenyl or naphthyl, said C3-C7 cycloalkyl, phenyl or naphthyl being optionally substituted by C1-C6 alkyl, phenyl, C1-C6 alkoxy-(C1-C6)-alkyl, R3R3Nxe2x80x94(C1-C6)-alkyl, fluoro-(C1-C6)-alkyl fluoro-(C1-C6)-alkoxy, C2-C5 alkanoyl, halo, xe2x80x94OR3, cyano, xe2x80x94COOR3, C3-C7 cycloalkyl, xe2x80x94S(O)mR4, xe2x80x94NR3R3, xe2x80x94SO2NR3R3, xe2x80x94CONR3R3, xe2x80x94NR3COR4 or xe2x80x94NR3SO2R4, with the proviso that R2 is not hydrogen when A is a bond, or (ii) when A is C2-C3 alkylene, xe2x80x94NR7R8, xe2x80x94OR3, xe2x80x94COOR3, xe2x80x94OCOR4, xe2x80x94SO2R4, xe2x80x94CN, xe2x80x94SO2N R3R3, xe2x80x94NR3COR4 or xe2x80x94CON R3R3, or (iii) a C-linked, 4 to 11 membered, mono or bicyclic heterocycle having either from 1 to 4 ring nitrogen atom(s) or 1 or 2 nitrogen and 1 oxygen or 1 sulphur ring atoms, optionally C-substituted by oxo, C1-C6 alkoxy-(C1-C6)-alkyl, R3R3Nxe2x80x94(C1-C6)-alkyl, fluoro-(C1-C6)-alkyl, fluoro-(C1-C6)-alkoxy, fluoro-(C2-C5)-alkanoyl, halo, cyano, xe2x80x94OR5, R6, xe2x80x94COR5, xe2x80x94NR5R5, xe2x80x94COOR5, S(O)mR6, xe2x80x94SO2NR5R5, xe2x80x94CONR5R5, xe2x80x94NR5SO2R6 or xe2x80x94NR5COR6 and optionally N-substituted by C1-C6 alkoxy-(C1-C6)-alkyl, R3R3Nxe2x80x94(C2-C6)-alkyl, fluoro-(C1-C6)-alkyl, fluoro-C2-C5)-alkanoyl, R6, xe2x80x94COR5, xe2x80x94COOR5, xe2x80x94S(O)mR6, xe2x80x94SO2NR5R5 or xe2x80x94CONR5R5;
R3 is H, C1-C6 alkyl, C3-C7 cycloalkyl or phenyl;
R4 is C1-C6 alkyl, C3-C7 cycloalkyl or phenyl;
R5 is H, C1-C6 alkyl, C3-C7 cycloalkyl, phenyl, naphthyl or het;
R6 is C1-C6 alkyl, C3-C7 cycloalkyl, phenyl, naphthyl or het;
either, R7 and R8, taken together with the nitrogen atom to which they are attached represent azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, homopiperidinyl, homopiperazinyl or tetrahydroisoquinolinyl, each being optionally substituted on a ring carbon atom by C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, C1-C6 alkoxy-(C1-C6)-alkyl, R3R3Nxe2x80x94(C1-C6)-alkyl, fluoro-(C1-C6)-alkyl, xe2x80x94CONR3R3, xe2x80x94COOR3 or C2-C5 alkanoyl, and optionally substituted on a ring carbon atom not adjacent to a ring nitrogen atom by fluoro-(C1-C6)-alkoxy, halo, xe2x80x94OR3, cyano, xe2x80x94S(O)mR4, xe2x80x94NR3R3, xe2x80x94SO2NR3R3, xe2x80x94NR3COR4 or xe2x80x94NR3SO2R4, and said piperazin-1-yl and homopiperazin-1-yl being optionally substituted on the ring nitrogen atom not attached to A by C1-C6 alkyl, phenyl, C1-C6 alkoxy-(C2-C6)-alkyl, R3R3Nxe2x80x94(C2-C6)-alkyl, fluoro-(C1-C6)-alkyl, C2-C5 alkanoyl, xe2x80x94COOR4, C3-C8 cycloalkyl, xe2x80x94SO2R4, xe2x80x94SO2NR3R3 or xe2x80x94CONR3R3, or, R7 is H, C1-C6 alkyl, C3-C8 cycloalkyl, phenyl or benzyl and R8 is H, C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, benzyl, fluoro-(C1-C6)-alkyl, xe2x80x94CONR3R3, xe2x80x94COOR4, C2-C5 alkanoyl or xe2x80x94SO2NR3R3;
m is 0, 1 or 2; and
xe2x80x9chetxe2x80x9d, used in the definitions of R5 and R6, means C-linked pyrrolyl, imidazolyl, triazolyl, thienyl, furyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, quinazolinyl, phthalazinyl, benzoxazolyl or quinoxalinyl, each optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, cyano or halo.
In the above definitions, halo means fluoro, chloro, bromo or iodo and alkyl, alkylene, alkanoyl and alkoxy groups containing the requisite number of carbon atoms can be unbranched or branched chain. The heterocycle as defined in R2, part (iii), above may be aromatic or fully or partially saturated. The expression xe2x80x98C-linkedxe2x80x99 used in the definition of R2 and xe2x80x9chetxe2x80x9d means that the group is linked to the adjacent atom by a ring carbon atom. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl. Examples of alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy and t-butoxy. Examples of alkylene include methylene, 1,1-ethylene, 1,2-ethylene, 1,3-propylene and 1,2-propylene. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
The pharmaceutically acceptable salts of the compounds of the formula (I) include the acid addition and the base salts thereof.
Suitable acid addition salts are formed from acids which form non-toxic salts and examples are the hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, saccharate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate and pamoate salts.
Suitable base salts are formed from bases which form non-toxic salts and examples are the sodium, potassium, aluminium, calcium, magnesium, zinc and diethanolamine salts.
For a review on suitable salts see Berge et al, J. Pharm. Sci., 66, 1-19 (1977).
The pharmaceutically acceptable solvates of the compounds of the formula (I) include the hydrates thereof.
Also included within the present scope of the compounds of the formula (I) are polymorphs thereof.
A compound of the formula (I) may contain one or more additional asymmetric carbon atoms and therefore exist in two or more stereoisomeric forms. The present invention includes the individual stereoisomers of the compounds of the formula (I) together with mixtures thereof.
Separation of diastereoisomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or H.P.L.C. of a stereoisomeric mixture of a compound of the formula (I) or a suitable salt or derivative thereof. An individual enantiomer of a compound of the formula (I) may also be prepared from a corresponding optically pure intermediate or by resolution, such as by H.P.L.C. of the corresponding racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid or base, as appropriate.
Preferably, R1 is C1-C6 alkyl optionally substituted by 1 or 2 substituents each independently selected from phenyl and naphthyl.
Preferably, R1 is C1-C6 alkyl substituted by 1 or 2 substituents each independently selected from phenyl and naphthyl.
Preferably, R1 is C1-C4 alkyl substituted by 1 or 2 substituents each independently selected from phenyl and naphthyl.
Preferably, R1 is C1-C2 alkyl substituted by 1 or 2 substituents each independently selected from phenyl and naphthyl.
Preferably, R1 is phenylethyl, diphenylethyl or naphthylmethyl.
Preferably, R1 is 2-phenylethyl, 2,2-diphenylethyl or 1-naphthylmethyl.
Preferably, A is a bond.
Preferably, A is C1-C3 alkylene.
Preferably, A is C2-C3 alkylene.
Preferably, A is C2 alkylene.
Preferably, A is xe2x80x94CH2CH2xe2x80x94.
Preferably, R2 is C1-C6 alkyl, phenyl or NR7R8.
Preferably, R2 is 2-methylprop-1-yl, phenyl or NR7R8.
Preferably, xe2x80x94Axe2x80x94R2 is 2-methylprop-1-yl, phenyl or xe2x80x94CH2CH2NR7R8.
Preferably, R7 is C1-C6 alkyl.
Preferably, R7 is C1-C3 alkyl.
Preferably, R7 is propyl.
Preferably, R7 is prop-2-yl.
Preferably, R8 is C3-C8 cycloalkyl.
Preferably, R8 is C3-C6 cycloalkyl.
Preferably, R8 is cyclopentyl.
Preferred heterocycles included in the definition of R2, part (iii) are pyrrolyl, imidazolyl, triazolyl, thienyl, furyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, quinazolinyl, phthalazinyl, benzoxazolyl, quinoxalinyl, 1,2-dihydroisoquinolinyl, 3,4-dihydroisoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl and piperazinyl.
Preferred examples of compounds of the formula (I) include those of the Examples section hereafter, including any pharmaceutically acceptable salts thereof.
The compounds of the formula (I) can be prepared by conventional routes such as by the procedures described in the general methods presented below or by the specific methods described in the Examples section, or by similar methods thereto. The present invention also encompasses these processes for preparing the compounds of formula (I), in addition to any novel intermediates used therein. In the general methods described, R1, R2 and A are as previously defined unless otherwise stated.
All the compounds of formula (I) may be prepared by the deprotection of a compound of formula 
wherein P1, P2 and P3 represent suitable protecting groups which may be the same or different or P1 and P2 optionally form part of the same protecting group. Examples of suitable protecting groups will be apparent to the skilled person [see for instance xe2x80x98Protecting Groups in Organic Synthesis (Second Edition)xe2x80x99, Theodora W. Green and Peter G. M. Wuts, John Wiley and Sons, 1991]. Preferred individual protecting groups are silyl (substituted with three groups independently selected from aryl and alkyl), alkanoyl and aroyl. A preferred protecting group where P1 and P2 form part of the same protecting group is where P1 and P2 taken together are C1-C6 alkylene. Particularly preferred individual protecting groups are acetyl and benzoyl. Suitable conditions for the deprotection are well known in the art [see for instance xe2x80x98Protecting Groups in Organic Synthesis (Second Edition)xe2x80x99, Theodora W. Green and Peter G. M. Wuts, John Wiley and Sons, 1991]. In a typical procedure, where P1, P2 and P3 are each acetyl, the protecting groups may be removed by treating a solution of the compound of formula (II) in a suitable solvent, such as a mixture of water and methanol, with a base such as sodium carbonate, typically at room temperature.
The protecting groups P1, P2 and P3 may be removed together in a single step or sequentially, in any order. Alternatively, any two of the protecting groups P1, P2 and P3 may be removed together in a single step and the remaining group may be removed in a separate step, in either order.
The compounds of formula (II) may be prepared according to the routes shown in Schemes 1 and 2, in which X is a leaving group, preferably chloro and P1, P2 and P3 are as defined above. 
In Scheme 1, compounds of the formula (II) may be prepared by the reaction of a compound of the formula (III) with a compound of the formula (IV) according to known methods. In a typical procedure, the compound of the formula (III) is heated with N,O-bis(trimethylacetamide) in an inert solvent such as 1,1,1-trichloroethane, the solvent is removed and a solution of the residue, in a suitable solvent such as toluene, is heated, preferably under reflux, with the compound of the formula (IV) and trimethylsilyltriflate. Compounds of the formula (IV) may be prepared by the hydrolysis of a compound of the formula (V). Typically, the compound of the formula (V) is dissolved in a suitable solvent, such as ethanol, and treated with an acid such as hydrochloric acid. The reaction is preferably performed from 0 to 100xc2x0 C., most preferably from 20 to 50xc2x0 C. Compounds of the formula (V) may be prepared by the sulphonylation of a compound of the formula (VI) with a compound of the formula (VII). In a typical procedure, a solution of the compound of the formula (VI) in a suitable inert solvent such as dichloromethane is treated with the compound of the formula (VII). An acid acceptor such as triethylamine may optionally be added. Compounds of the formula (VI) may be prepared by the reduction of a compound of the formula (VII). The reduction may be carried out with any suitable hydride reducing agent or by hydrogenation. In a typical procedure, a solution of the compound of the formula (VIII) in a suitable solvent such as ethanol is saturated with ammonia gas, treated with an appropriate hydrogenation catalyst such as Pearlmann""s catalyst and pressurised with hydrogen, preferably to about 414 kPa (60 psi). Compounds of the formula (VIII) may be prepared by reacting a compound of the formula (IX) with a source of cyanide anion such as potassium cyanide. The reaction is typically carried out in a solvent such as N,N-dimethylformamide at an elevated temperature. Compounds of the formula (IX) may be prepared by the oxidation of a compound of the formula (X). In a typical procedure, an aqueous solution of potassium peroxymonosulphate is added to a solution of the compound of the formula (X) and sodium hydrogencarbonate in a suitable solvent, such as a mixture of water and acetone. Compounds of the formula (X) may be prepared by the displacement of chloride in a compound of the formula (XI) with thiomethoxide. Typically, the reaction is carried out in a polar solvent such as N,N-dimethylformamide, at elevated temperatures and under an atmosphere of nitrogen. Thiomethoxide is used as an alkali metal salt such as sodium thiomethoxide. Compounds of the formula (XI) may be prepared by the reaction of a compound of the formula (XII) with an appropriate primary amine. Typically, a solution of the dichloropurine (XII) in a solvent such as isopropyl alcohol is treated with the amine and heated under reflux. An additional acid acceptor such as diphenylethylamine may optionally be added. Compound (XII) may be prepared by the reaction of 2,6-dichloro-9H-purine (XIII) with dihydropyran in a suitable solvent such as ethyl acetate and in the presence of an acid catalyst such as 4-toluenesulphonic acid, usually at an elevated temperature. 
In Scheme 2, compounds of the formula (II) may be prepared by the sulphonylation of a compound of the formula (XIV) with a compound of the formula (VII). In a typical procedure, a solution of the compound of the formula (XIV) in a suitable inert solvent such as dichloromethane is treated with the compound of the formula (VII). An acid acceptor such as triethylamine may be optionally added. Compounds of the formula (XIV) may be prepared by the reduction of a compound of the formula (XV). The reduction may be carried out with any suitable hydride reducing agent or by hydrogenation. In a typical procedure, a solution of the compound of the formula (XV) in a suitable solvent, such as ethanol, is saturated with ammonia gas, treated with an appropriate hydrogenation catalyst such as 5% w/w palladium on charcoal and pressurised with hydrogen, preferably to 1034 kPa (150 psi). Compounds of the formula (XV) may be prepared by the reaction of a compound of the formula (XVI) with an appropriate primary amine. Typically, a solution of the compound (XVI) in a suitable solvent such as acetonitrile is treated with the amine at room temperature. An additional acid acceptor such as diphenylethylamine may optionally be added. Compounds of the formula (XVI) may be prepared by the substitution of the iodo group in a compound of the formula (XVII) with cyanide. Typically, a solution of the compound of the formula (XVII) in a suitable solvent (e.g. N,N-dimethylformamide) is treated with copper(II)cyanide and heated, preferably at a temperature in excess of 100xc2x0 C. Compounds of the formula (XVII) are known in the art (e.g. see J. Med. Chem., 1992, 35, 248 where P1, P2 and P3 are each acetyl).
Alternatively, the compounds of the formula (I) may be prepared according to Scheme 3, wherein X is a leaving group, preferably chloro, by sulphonylation of a compound of formula (XVIII) with a compound of the formula (VII). 
In a typical procedure, the compound of formula (XVIII) is dissolved in a suitable solvent such as 1,4-dioxan or tetrahydrofuran (with heating if necessary) and treated, typically at room temperature and under an atmosphere of nitrogen, with a sulphonylating agent of the formula (VII), optionally in the presence of an acid acceptor (e.g. triethylamine). Compounds of the formula (XVIII) may be prepared by the reduction of a compound of the formula (XIX). The reduction may be carried out with any suitable hydride reducing agent or by hydrogenation. In a typical procedure, a solution of the compound of formula (XIX) in a suitable solvent such as ethanol is saturated with ammonia gas, treated with an appropriate hydrogenation catalyst such as 5% w/w palladium on charcoal and pressurised with hydrogen, preferably to 1034 kPa (150 psi). Compounds of the formula (XIX) may be prepared by the deprotection of a compound of the formula (XV) according to methods known in the art [see for instance xe2x80x98Protecting Groups in Organic Synthesis (Second Edition)xe2x80x99, Theodora W. Green and Peter G. M. Wuts, John Wiley and Sons, 1991]. The protecting groups may be removed together, individually or in any combination thereof. In a typical example, where P1, P2 and P3 are each acetyl, a solution of the compound of the formula (XV) in a suitable solvent such as ethanol is treated with a base such as ammonia at room temperature. In certain cases, deprotection and reduction of a compound of the formula (XV) to furnish a compound of the formula (XVIII) may be conveniently carried out together under reducing conditions. In a typical example, the compound of the formula (XV) is dissolved in a suitable solvent such as ethanol and the solution is saturated with ammonia prior to treatment with an appropriate hydrogenation catalyst such as palladium on carbon and pressurisation with hydrogen to 1034 kPa (150 psi).
Compounds of the formula (I) in which A is xe2x80x94CH2CH2xe2x80x94 and R2 is NR7R8 may also be prepared by the route shown in Scheme 4. 
In Scheme 4, compounds of the formula (I) in which A is xe2x80x94CH2CH2xe2x80x94 and R2 is xe2x80x94NR7R8 may be prepared by the reaction of a compound of the formula (XX) with a compound of the formula
R7R8NHxe2x80x83xe2x80x83(XXII).
In a typical procedure, the compound of the formula (XX) and the compound of the formula (XXII) are mixed, optionally in the presence of a suitable solvent. Preferably, the reaction mixture is heated, most preferably at the reflux temperature of the compound of the formula (XXII). Compounds of the formula (XXII) are either commercially available or easily prepared using standard procedures well known to those skilled in the art (e.g. the reductive condensation of an amine with a ketone or an aldehyde). Compounds of the formula (XX) may be prepared by the condensation of a compound of the formula (XVIII) with 2-chloroethanesulphonyl chloride. In a typical procedure, a solution of the compound of the formula (XVIII) and a base, preferably a tertiary amine base such as triethylamine, in a suitable solvent, such as dichloromethane, is treated with 2-chloroethanesulphonyl chloride. Compounds of the formula (XVIII) may be prepared by the deprotection of a compound of the formula (XIV) in which protecting groups P1, P2 and P3 are as defined above. The protecting groups may be removed together, or singly in any combination thereof. Suitable conditions for the deprotection are well known in the art [see for instance xe2x80x98Protecting Groups in Organic Synthesis (Second Edition)xe2x80x99, Theodora W. Green and Peter G. M. Wuts, John Wiley and Sons, 1991]. In a typical procedure, where P1, P2 and P3 are each acetyl, the protecting groups may be removed by treating a solution of the compound of formula (XIV) in a suitable solvent, such as a mixture of water and methanol, with a base such as sodium carbonate, typically at room temperature.
Compounds of the formula (I) may also be interconverted using conventional functional group interconversion techniques.
All of the reactions and the preparations of novel starting materials used in the preceding methods are conventional and appropriate reagents and reaction conditions as well as procedures for isolating the desired products will be well-known to persons skilled in the art with reference to literature precedents and the Examples and Preparations sections below.
A pharmaceutically acceptable salt of a compound of the formula (I) may be readily prepared by mixing together solutions of a compound of the formula (I) and the desired acid or base, as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
The anti-inflammatory properties of the compounds of the formula (I) are demonstrated by their ability to inhibit neutrophil function which indicates A2a receptor agonist activity. This is evaluated by determining the compound profile in an assay where superoxide production is measured from neutrophils activated by fMLP. Neutrophils were isolated from human peripheral blood using dextran sedimentation followed by centrifugation through Ficoll-Hypaque solution. Any contaminating erythrocytes in the granulocyte pellet were removed by lysis with ice-cold distilled water. Superoxide production from the neutrophils was induced by fMLP in the presence of a priming concentration of cytochalasin B. Adenosine deaminase was included in the assay to remove any endogenously produced adenosine that might suppress superoxide production. The effect of the compound on the fMLP-induced response was monitored colorometrically from the reduction of cytochrome C within the assay buffer. The potency of the compounds was assessed by the concentration giving 50% inhibition (IC50) compared to the control response to fMLP.
The compounds of the formula (I) can be administered alone but will generally be administered in admixture with a suitable pharmaceutical excipient, diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
For example, the compounds of the formula (I) can be administered orally, buccally or sublingually in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed-, sustained-, pulsed- or controlled-release applications.
Such tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.
Solid compositions of a similar type may also be employed as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or a high molecular weight polyethylene glycol. For aqueous suspensions and/or elixirs, the compounds of the formula (I) may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol or glycerin, and combinations thereof.
The compounds of the formula (I) can also be administered parenterally, for example, intravenously, intra-arterially, intraperitoneally, intrathecally, intraventricularly, intrasternally, intracranially, intramuscularly or subcutaneously, or they may be administered by infusion techniques. They are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.
For oral and parenteral administration to human patients, the daily dosage level of the compounds of the formula (I) will usually be from 0.01 to 100 mg/kg, preferably from 0.1 to 100 mg/kg (in single or divided doses).
Thus tablets or capsules of the compound of the formula (I) may contain from 5 to 500 mg of active compound for administration singly or two or more at a time, as appropriate. The physician in any event will determine the actual dosage which will be most suitable for any individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited and such are within the scope of this invention.
The compounds of formula (I) can also be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomiser or nebuliser, with or without the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA 134A [trade mark]) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA [trade mark]), carbon dioxide or other suitable gas. In the case of a pressurised aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurised container, pump, spray, atomiser or nebuliser may contain a solution or suspension of the active compound, e.g. using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e.g. sorbitan trioleate. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of a compound of the formula (I) and a suitable powder base such as lactose or starch.
Aerosol or dry powder formulations are preferably arranged so that each metered dose or xe2x80x9cpuffxe2x80x9d contains from 20 to 4000 xcexcg of a compound of the formula (I) for delivery to the patient. The overall daily dose with an aerosol will be in the range of from 20 xcexcg to 20 mg which may be administered in a single dose or, more usually, in divided doses throughout the day.
Alternatively, the compounds of the formula (I) can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder. The compounds of the formula (I) may also be transdermally administered, for example, by the use of a skin patch.
For application topically to the skin, the compounds of the formula (I) can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
The compounds of the formula (I) may also be used in combination with a cyclodextrin. Cyclodextrins are known to form inclusion and non-inclusion complexes with drug molecules. Formation of a drug-cyclodextrin complex may modify the solubility, dissolution rate, bioavailability and/or stability property of a drug molecule. Drug-cyclodextrin complexes are generally useful for most dosage forms and administration routes. As an alternative to direct complexation with the drug the cyclodextrin may be used as an auxiliary additive, e.g. as a carrier, diluent or solubiliser. Alpha-, beta- and gammacyclodextrins are most commonly used and suitable examples are described in WO-A-91/11172, WO-A-94/02518 and WO-A-98/55148.
It is to be appreciated that all references herein to treatment include curative, palliative and prophylactic treatment.
Thus the invention provides:
(i) a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof;
(ii) a process for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof;
(iii) a pharmaceutical composition including a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable excipient, diluent or carrier;
(iv) a compound of the formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof, for use as a medicament;
(v) the use of a compound of the formula (I) or of a pharmaceutically acceptable salt, solvate or composition thereof, for the manufacture of a medicament to treat a disease for which a A2a receptor agonist is indicated;
(vi) the use of a compound of the formula (I) or of a pharmaceutically acceptable salt, solvate or composition thereof, for the manufacture of an anti-inflammatory agent;
(vii) the use of a compound of the formula (I) or of a pharmaceutically acceptable salt, solvate or composition thereof, for the manufacture of a medicament for the treatment of a respiratory disease;
(viii) use as in (vii) where the disease is selected from the group consisting of adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, bronchiectasis, chronic sinusitis and rhinitis;
(ix) the use of a compound of the formula (I) or of a pharmaceutically acceptable salt, solvate or composition thereof, for the manufacture of a medicament for the treatment of septic shock, male erectile dysfunction, hypertension, stroke, epilepsy, cerebral ischaemia, peripheral vascular disease, post-ischaemic reperfusion injury, diabetes, rheumatoid arthritis, multiple sclerosis, psoriasis, allergic dermatitis, eczema, ulcerative colitis, Crohns disease, inflammatory bowel disease, Heliobacter pylori-gastritis, non-Heliobacter pylon gastritis, non-steroidal anti-inflammatory drug-induced damage to the gastrointestinal tract or a psychotic disorder, or for wound healing;
(x) a method of treatment of a mammal, including a human being, to treat a disease for which a A2a receptor agonist is indicated including treating said mammal with an effective amount of a compound of the formula (I) or with a pharmaceutically acceptable salt, solvate or composition thereof;
(xi) a method of treatment of a mammal, including a human being, to treat an inflammatory disease including treating said mammal with an effective amount of a compound of the formula (I) or with a pharmaceutically acceptable salt, solvate or composition thereof;
(xii) a method of treatment of a mammal, including a human being, to treat a respiratory disease including treating said mammal with an effective amount of a compound of the formula (I) or with a pharmaceutically acceptable salt, solvate or composition thereof;
(xiii) a method as in (xii) where the disease is selected from the group consisting of adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, bronchiectasis, chronic sinusitis and rhinitis;
(xiv) a method of treatment of a mammal, including a human being, to treat septic shock, male erectile dysfunction, hypertension, stroke, epilepsy, cerebral ischaemia, peripheral vascular disease, post-ischaemic reperfusion injury, diabetes, rheumatoid arthritis, multiple sclerosis, psoriasis, allergic dermatitis, eczema, ulcerative colitis, Crohns disease, inflammatory bowel disease, Heliobacter pylori-gastritis, non-Heliobacter pylon gastritis, non-steroidal anti-inflammatory drug-induced damage to the gastrointestinal tract or a psychotic disorder, or for wound healing, including treating said mammal with an effective amount of a compound of the formula (I) or with a pharmaceutically acceptable salt, solvate or composition thereof; and
(xv) certain novel intermediates disclosed herein.
The following Examples illustrate the preparation of the compounds of the formula (I):
1H Nuclear magnetic resonance (NMR) spectra were in all cases consistent with the proposed structures. Characteristic chemical shifts (xcex4) are given in parts-per-million downfield from tetramethylsilane using conventional abbreviations for designation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. The mass spectra (m/z) were recorded in the thermospray ionisation mode. The following abbreviations have been used for common solvents: CDCl3, deuterochloroform; DMSO, dimethylsulphoxide. The abbreviation psi means pounds per square inch. Where thin layer chromatography (TLC) has been used it refers to silica gel TLC using silica gel 60 F254 plates, Rf is the distance travelled by a compound divided by the distance travelled by the solvent front on a TLC plate. The abbreviation Ac has been used in place of acetyl and TBDMS means tert-butyldimethylsilyl.